PROJECT SUMMARY Multiple population and community based studies conducted across the US, Europe, Japan, and Australia all have repeatedly observed complex neuropathologic changes in individuals with a clinical diagnosis of Alzheimer's disease (AD) dementia. Although usually including neuritic plaques (NP) and neurofibrillary tangles (NFT), the regional levels and extent of distribution of these hallmark lesions are variable. Additionally, more than half of individuals with AD dementia have other comorbid lesions in brain that when present in isolation can be diagnostic of dementia?the AD-Related Dementias (ADRDs). These include cerebral amyloid angiopathy (CAA), vascular brain injury (VBI), Lewy body disease (LBD), and hippocampal sclerosis of the elderly (HS), among others. Indeed, individuals with a clinical diagnosis of AD dementia frequently show a complex mix of AD lesions and comorbid lesions, making it unclear the extent to which each contributed to cognitive decline and dementia in that person. We hypothesize that the mechanisms of injury and response to injury that produce these different disease-specific brain lesions are influenced by differing genetic factors. With few exceptions, genetic studies for AD have associated genetic variants with a clinical diagnosis of AD dementia. The comorbid complexity described above is a serious limitation to interpreting these data. Are the associations with AD dementia related to the hallmark lesions of AD (common assumption), the variably present comorbid lesions, or both? Only two studies have attempted to address this limitation. As a core analysis of the Alzheimer Disease Genetics Consortium (U01AG032984), our study of AD neuropathologic changes was the larger of these studies with approximately 4900 brain autopsies. However, even this initial study was limited by sample size, platform, and less sophisticated analysis tools. To address these limitations and to advance our knowledge of the full spectrum of dementia neuropathology, we propose a genomics study of hallmark AD lesions together with comorbid lesions associated with ADRDs. This study will expand the sample size of neuropathology subjects, will expand efforts to include next-generation sequence data, and will implement more advanced statistical techniques to better understand the relationships between traits. When successfully completed, our results will point to novel, relevant molecular contributors for each of the pathologic lesions of AD or ADRDs, either alone or in combination. To accomplish these goals we propose four Specific Aims. SA1: Identify genetic variants associated with hallmark AD lesions by whole genome sequencing and genome-wide genotyping; SA2: Identify genetic variants associated with comorbid lesions commonly present in brains of older individuals; SA3: Determine the inter-trait genetic landscape by assessing confounding and genetic correlations across traits; and, SA4: Determine regional, cellular, and lesion distribution of protein products of selected genes identified in SA1-2.